2-(3-Aminopropyl)-2,4-dihydro-6-phenyl-1H-s-triazolo{8 4,3-a{9 {8 1,4{9 benzodiazepin-1-ones and method of treatment therewith

ABSTRACT

Therapeutic compositions for treating humans and animals comprising, in dosage unit form, a 2-(3-aminopropyl)-2,4-dihydro6-phenyl-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one of the Formula I;   wherein R and R1 are selected from the group consisting of hydrogen and alkyl of one to three carbon atoms, inclusive, or the group   IS A HETEROCYCLIC RING SELECTED FROM THE GROUP CONSISTING OF PYRROLIDINO, PIPERIDINO, MORPHOLINO, PIPERAZINO, 4METHYLPIPERAZINO,4-(2-HYDROXYETHYL)PIPERAZINO, AND 4PHENYLPIPERAZINO; WHEREIN R2 is selected from the group consisting of fluorine, chlorine, and bromine and wherein R3 is selected from the group consisting of fluorine, chlorine, bromine, nitro, and trifluoromethyl, including the pharmacologically acceptable acid addition salts thereof in combination with a pharmaceutical carrier. The compositions are useful as psychic energizers and antidepressants for treatment of depressed and anxious states. The compositions can be administered to human or animal subjects.

United States Patent [1 1 Hester, Jr.

I45} Feb. 18,1975

I 2-(3-AMINOPROPYL)-2,4-DlHYDRO-6- PHENYL-lH-S-TRIAZOLO[4,3-A][1,4]BENZODIAZEPIN-l-ONES AND METHOD OF TREATMENT THEREWITH [75]Inventor: Jackson B. Hester, .lr., Galesburg,

Mich.

[731 Assignee: The Upjohn Company, Kalamazoo.

Mich.

[22] Filed: Aug. 14, 1972 [21] Appl. No.: 280,158

[52] U.S. Cl 424/248, 424/250, 424/267,

424/269 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/248, 250, 244,273,

[56] References Cited UNITED STATES PATENTS 3,201,404 8/l965 Ruschig etal. 260/308 C 3.514.466 5/1970 St'zihle ct al. 260/308 C 3,644.3342/1972 Ning cl al. 260/239.30 3,646,055 2/l972 Hester 260/308 C FOREIGNPATENTS OR APPLICATIONS 771,756 12/1971 Belgium Primary Examiner-StanleyJ. Friedman Attorney, Agent, or Firm-John J. Killinger; RomanSaliwanchik [57] ABSTRACT Therapeutic compositions for treating humansand animals comprising, in dosage unit form, a 2-(3-aminopropyl)-2,4-dihydro-6-phenyl-l I-l-s-triazolo[4,3-a][l,4]benzodiazepin-l-one of the Formula 1:

Formula I wherein R and R are selected from the group consistmg ofhydrogen and alkyl of one to three carbon atoms, inclusive, or the groupis a heterocyclic ring selected from the group 665515; 7

The compositions can be administered to'human or animal subjects.

9 Claims, No Drawings 1 2-(3-AMINOPROPYL)-2,4-DIHYDRO-6-PHENYL-lH-S-TRIAZOLO[4,3-A][1,41BENZODIAZEPIN- l-ONES AND METHOD OF TREATMENTTHEREWITH CROSS REFERENCE TO RELATED APPLICATIONS The active compoundsof the present invention and their preparation are disclosed incopending US. application Ser. No. 204,680, filed Dec. 3, 197l.

BRIEF SUMMARY OF THE INVENTION This invention is a therapeuticcomposition for treating humans and animals comprising a benzodiazepineof the Formula I and including the pharmacologically acceptable acidaddition salts thereof in combination with a pharmaceutical carrier anda method for treating depression and anxiety.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the Formula I canbe prepared by methods disclosed in copending application Ser. No.204,680, filed Dec. 3, I971.

The compositions of the present invention are presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, sterile parenteralsolutions or suspensions, and oral solutions or suspensions, andoil-in-water and water-in-oil emulsions containing suitable quantitiesof the compound of Formula I.

For oral administration either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof Formula I is mixed with conventional ingredients such as talc,magnesium stearate, dicalcium phosphate, magnesium aluminum silicate,calcium sulfate, starch, lactose, acacia, methylcellulose, andfunctionally similar materials as pharmaceutical diluents or carriers.Wafers are prepared in the same manner as tablets, differing only inshape and the inclusion of sucrose or other sweetener and. flavor. Intheir simplest embodiment, capsules, like tablets, are prepared bymixing the compound with an inert pharmaceutical diluent and filling themixture into a hard gelatincapsule of appropriate size. Soft gelatincapsules are prepared by machine encapsulation of a slurry of thecompound with an acceptable vegetable oil, light liquid petrolatum orother inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs,and suspensions can be prepared. The water-soluble forms can bedissolved in an aqueous vehicle together with sugar, aromatic flavoringagents and preservatives to form a syrup. An elixir is prepared by usinga hydro-alcoholic (ethanol) vehicle with suitable sweeteners such assugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with a syrup vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle. water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilizedbefore filling into a suitable vial or ampul and sealing.Advantageously, adjuvants such as a local anesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection issupplied to reconstitute the liquid prior to use, Parenteral suspensionsare prepared in substantially the same manner except that the compoundis suspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The compound can be sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

The term unit dosage form, as used in the specification and claims,refers to physically discrete units suitable as unitary dosages forhuman subjects and animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticaldiluent, carrier, or vehicle. The specifications for the novel unitdosage forms of this invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulareffect to be achieved, and (b) the limitations inherent in the art ofcompounding such an active material for use in humans and animals, asdisclosed in detail in this specification, these being features of thepresent invention. Examples of suitable unit dosage forms in accord withthis invention are tablets, capsules, pills, suppositories, powderpackets, granules, wafers, cachets, teaspoonsful, tablespoonsful,droppersful, ampules, vials, segregated multiples of any of theforegoing, and other forms as-herein described.

The dosage of the compound for treatment depends on route ofadministration, the age, weight, and condition of the patient. A dosageschedule of from about 5 to 300 mg. in a single dose, embraces theeffective range to alleviate depression for which the compositions areeffective. The dosage to be administered is calculated on the basis offrom about 0.07 to about 4.5 mg./kg. by weight of subject.

The compound is compounded with a suitable pharmaceutical carrier inunit dosage form for convenient and effective administration. In thepreferred embodiments of this invention, the dosage units contain thecompound in: 5, 1O, 25, I00, and 250 mg. amounts for systemic treatment,and 0.1% to 5.0% w/v for parenteral treatment. The dosage ofcompositions containing a compound of Formula I and one or more otheractive ingredients is to be determined with reference to the actualdosage of each such ingredient.

In addition to the administration of a compound of Formula I as theprinciple active ingredient of compositions for treatment of theconditions described herein, the said compound can be combined withother compounds to obtain advantageous combinations of properties.

The following examples are illustrative of the best mode contemplated bythe inventor for carrying out his invention and are not to be construedas limiting.

EXAMPLE I A lot of 10,000 tablets, each containing 5.0 mg. of8-chloro-6-(o-chlorophenyl)-2-[3- (dimethylamino)propyl l-2,4-dihydro-lH-striazolo[4,3-a][l,4]benzodiazepin-l-one is prepared from thefollowing types and amounts of ingredients:

8-chloro-fi-(o-chlorophenyl)- 2-[3-(dimethylamin0)propyll- ZA-dihydro-lH-s-triazolo- [4.3-all l .4lbenzodiazepin- [-one 50 gm. Dicalciumphosphate 1,500 gm. Methylcellulose. U.S.P. (l cps.) 60 gm. Talc 150 gm.(orn Starch 200 gm. Magnesium stearate 12 gm.

The compound and dicalcium phosphate are mixed well, granulated with 7.5percent solution of methylcellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the tale, starch and magnesiumstearate, and compressed into tablets.

These tablets are useful in reducing depression and anxiety in adults ata dose of one to two tablets, depending on the age and weight of thepatient.

EXAMPLE 2 One thousand two-piece hard gelatin capsules, each containing100 mg. of 8-chloro-6-(o-chlorophenyl)-2[3-(dimethylamino)propyl]-2,4-dihydro-lH-striazolo[4,3-a][ l,4]-benzodiazepin- 1 -one hydrobromide are prepared from the followingtypes and amounts of ingredients:

8-chloro-6-(o-chlorophenyl)- 2-13-(dimethylamino)propyl]- 2.4-dihydro-lH-s-triazolo- [4.3-all1.4lbenzodiazepinl-onc hydrobromidc 100 gm. Talc25 gm. Magnesium stearate 250 gm.

The ingredients are mixed well and filled into capsules of the propersize.

Capsules so prepared are useful for treating depression and anxiety inadults at a dose of one capsule.

EXAMPLE 3 One thousand tablets for sublingual use are prepared from thefollowing ingredients:

ll-chlorolw-to-chlorophenyH- 2-1 3-( dimethylamino )propyl] ZA-dihydro-lH-s-triazolo- [4.3-a1l1.4]benzodiazepinl-one 5 gm. Polyethylene glycol4.000.

powdered l50 gm. Polyethylene glycol 6.000.

powdered 75 gm.

The ingredients are mixed well and compressed .into sublingual-typetablets weighing 226 mg.

These tablets placed under the tongue are useful to reduce depressionand anxiety with a rapid induction at a dose of one tablet.

EXAMPLE 4 Soft gelatin capsules for oral use. each containing mg. of8-chloro-6-(o-chlorophenyl )2-[ 3-(dimcthylamino)propyl1-2.4-dihydro-lH-striazolol4,3-a][l,4lhenzodiazepin-lone are prepared by first dispersing the micronizedcompound in corn oil to render the material capsulatable and thenencapsulating in the usual manner.

EXAMPLE 5 One thousand tablets, each containing mg. of 8-chloro-6-(o-chlorophenyl)-2-[3- 4(dimethylamino)propyl]-2,4-dihydro-1H-striazolo[4,3-a][1,4]benzodiazepin-l-oneare made from the following types and amounts of ingredients:

ll.4lbenzodiazepin-l-one 25 gm. Lactose 355 gm. Microcrystallinecellulose NF gm. Starch 16 gm. Magnesium stearate powder 4 gm.

The ingredients are screened and blended together and pressed intotablets.

The tablets are useful to overcome depression and anxiety.

EXAMPLE 6 A sterile preparation suitable for intramuscular injection andcontaining 5 mg. of8-chloro-6-(ochlorophenyl)-2-[3-(dimethylamino)propyl]-2.4-dihydro-lH-s-tria2olo[4,3-a]-[1,4]benzodiazepinl-one in each milliliteris prepared from the following ingredients:

Ione 5 gm. Benzyl benzoate 200 ml. Methylparaben 1.5 gm. Propylparaben0.5 gm. Cottonseed oil qs L000 nil.

One milliliter of this sterile preparation is injected to reducedepression and anxiety in adults.

EXAMPLE 7 lH-s-triazolo[4,3-a][1,4]benzodiazepin-l-one; 8-chloro-6-(o-ehlorophenyl)-2-[3-(4- methylipiperazinmpropyl]-2,4-dihydro-l H-striazolo[4,3-a][1,4]benzodiazepin-l-one; and -8-chloro-6-(o-chlorophenyl)-2-l3 (methylamino)propyl1-2.4-dihydrolH-s-triazolo[4,3- a][ l,4]benzodiazepin-l-one for the8-chloro-6-(ochlorophenyl)-2-l 3-(dimethylaminolpropyl ]-2,4- dihydro-lH-s-triazolo[4,3-a|l l,4-henzodia'/.epinl-one.

I claim:

1. A process for treating depression and anxiety comprising theadministration to a depressed or anxietar human or animal subject offrom about 5 to about 300 mg. of a compound of the formula:

Formula I wherein R and R are selected from the group consisting ofhydrogen and alkyl of one to three carbon atoms, inclusive; or the groupis a heterocyclic ring selected from the group consisting ofpyrrolidino, piperidino, morpholino, piperazino, 4- methylpiperazino,4-(Z-hydroxyethyl)piperazino, and 4-phenylpiperazino; wherein R isselected from the group consisting of fluorine, chlorine, and bromineand wherein R is selected from the group consisting of fluorine.chlorine, bromine, nitro, and trifluoromethyl, or a pharmacologicallyacceptable acid addition salt thereof in association with apharmaceutical carrier.

2. The process of claim 1 wherein the compound is 8-chloro-o-(ochlorophenyl)-2-[3- (dimethylamino)propyl ]-2,4-dihydrolH-striazolo[4.3- l,4lbenzodiazepin-l-one and the amount administered isfrom about to about 300 mg. 3. The process of claim 1 wherein thecompound is 6 8-chloro-6-(o-chlorophenyl)-2-[3- (diethylamino))propyl]2,4-dihydro-lH-s-tria2olo[4,3-a][1,4]ben2odiazepinl-one and the amountadministered is from about 5 to about 300 mg.

4. The process of claim 1 wherein the compound is8-chloro6-(o-chlorophenyl)-2-[3- (pyrrolidino)propyl]2,4-dihydro-lH-s-triazolo[4,3- a][1,4]benzodiazepin-l-one and the amount administeredis from about 5 to about 300 mg.

5. The process of claim 1 wherein the compound is8-chloro-6-(o-chlorophenyl)-2-[3- (piperidino )propyl ]-2,4-dihydrolH-s-triazolol 4,3- a][1,4]benzodiazepin-l-one and the amountadministered is from about 5 to about 300 mg.

6. The process of claim 1 wherein the compound is8-chloro-6-(o-chlorophenyl)-2-[3(morpholino)propyl]-2,4-dihydro-lHs-triazolo[4,3-a][l,4]benzodiazepinl-one and the amount administered is from about 5 toabout 300 mg.

7. The process of claim 1 wherein the compound is8-chloro-6-(o-chlorophenyl)-2-[3- (piperazino )propyl ]-2,4-dihydrolH-s-triazolo[4,3- a][1,4]benzodiazepin-l-one and the amount administeredis from about 5 to about 300 mg.

8. The process of claim 1 wherein the compound is8-chloro-6-(o-chlorophenyl)-2-[3-(4-methylpiperazino)propyl]-2,4-dihydro-l"H-striazolo[4,3-a][1,4]benzodiazepin-l-oneand the amount administered is from about 5 to about 300 mg.

9. The process of claim I wherein the compound is8-c'hl0ro-6-(o-chlorophcnyl )-2-[3- (methylamino)propyl ]-2,4-dihydro-lH-s-triazolo[ 4,3- a][ 1,4]benzodiazepin-l-one and the amount administered is from about 5 to about 300 mg.

1. A PROCESS FOR TREATING DEPRESSION AND ANXIETY COMPRISING THEADMINISTRATION TO A DEPRESSED OR ANXIETAR HUMAN OR ANIMAL SUBJECT OFFROM ABOUT 5 TO ABOUT 300 MG, OF A COMPOUND OF THE FORMULA:
 2. Theprocess of claim 1 wherein the compound is8-chloro-6-(o-chlorophenyl)-2-(3-(dimethylamino)propyl)-2,4-dihydro-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one and the amount administered isfrom about 5 to about 300 mg.
 3. The process of claim 1 wherein thecompound is8-chloro-6-(o-chlorophenyl)-2-(3-(diethylamino)propyl)-2,4-dihydro-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one and the amount administered isfrom about 5 to about 300 mg.
 4. The process of claim 1 wherein thecompound is8-chloro-6-(o-chlorophenyl)-2-(3-(pyrrolidino)propyl)-2,4-dihydro-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one and the amount administered isfrom about 5 to about 300 mg.
 5. The process of claim 1 wherein thecompound is8-chloro-6-(o-chlorophenyl)-2-(3-(piperidino)propyl)-2,4-dihydro-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one and the amount administered isfrom about 5 to about 300 mg.
 6. The process of claim 1 wherein thecompound is8-chloro-6-(o-chlorophenyl)-2-(3-(morpholino)propyl)-2,4-dihydro-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one and the amount administered isfrom about 5 to about 300 mg.
 7. The process of claim 1 wherein thecompound is8-chloro-6-(o-chlorophenyl)-2-(3-(piperazino)propyl)-2,4-dihydro-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one and the amount administered isfrom about 5 to about 300 mg.
 8. The process of claim 1 wherein thecompound is8-chloro-6-(o-chlorophenyl)-2-(3-(4-methylpiperazino)propyl)-2,4-dihydro-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one and the amount administeredis from about 5 to about 300 mg.
 9. The process of claim 1 wherein thecompound is8-chloro-6-(o-chlorophenyl)-2-(3-(methylamino)propyl)-2,4-dihydro-1H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-one and the amount administered isfrom about 5 to about 300 mg.